Outcomes of lung transplantation for pleuroparenchymal fibroelastosis: a French multicentric retrospective study.

BACKGROUND: Pleuroparenchymal fibroelastosis (PPFE) has no currently available specific treatment. Benefits of lung transplantation (LT) for PPFE are poorly documented. METHODS: We conducted a nation-wide multicentric retrospective study in patients who underwent lung or heart-lung transplantation for chronic end-stage lung disease secondary to PPFE between 2012 and 2022 in France. RESULTS: Thirty-one patients were included. At transplantation, median age was 48 years [IQR 35 - 55]. 64.5% were women. Twenty-one (67.7%) had idiopathic PFFE. Sixteen (52%) had bilateral LT, 10 (32%) had single LT, 4 (13%) had lobar transplantation and one (3%) had heart-lung transplantation. Operative mortality was 3.2%. Early mortality (< 90 days or during the first hospitalization) was 32%. Eleven patients (35.5%) underwent reoperation for hemostasis. Eight (30.8%) experienced bronchial complications. Mechanical ventilation time was 10 days [IQR 2-55]. Length of stay in intensive care unit and hospital were 34 [IQR 18-73] and 64 [IQR 36-103] days, respectively. Median survival was 21 months. Post-transplant survival rates after 1, 2, and 5 years were 57.9%, 42.6% and 38.3% respectively. Low albuminemia (p=0.046), FVC (p=0.021), FEV1 (p=0.009) and high emergency lung transplantation (p=0.04) were associated with increased early mortality. Oversized graft tended to be correlated to a higher mortality (p=0.07). CONCLUSION: LT for PPFE is associated with high post-operative morbi-mortality rates. Patients requiring high emergency lung transplantation with advanced disease, malnutrition, or critical clinical status experienced worse outcomes. GOV IDENTIFIER: NCT05044390.

Donor to recipient age matching in lung transplantation: a European experience.

BACKGROUND: The age profile of organ donors and patients on lung transplantation (LT) waiting lists have changed over time. In Europe, the donor population has aged much more rapidly than the recipient population, making allocation decisions on lungs from older donors common. In this study we assessed the impact of donor and recipient age discrepancy on LT outcomes in the UK and France. METHODS: A retrospective analysis of all adult single or bilateral LT in France and the UK between 2010 and 2021. Recipients were stratified into 3 age groups: young (≤ 30 years), middle-aged (30 to 60) and older (≥60). Their donors were also stratified into 2 groups <60, ≥ 60. Primary graft dysfunction (PGD) rates and recipient survival was compared between matched and mismatched donor and recipient age groups. Propensity matching was employed to minimize covariate imbalances and to improve the internal validity of our results. RESULTS: Our study cohort was 4,696 lung transplant recipients (LTRs). In young and older LTRs, there was no significant difference in 1 and 5-years post-transplant survival dependent on the age category of the donor. Young LTRs who received older donor grafts had a higher risk of severe grade 3 PGD. CONCLUSION: Our findings show that clinically usable organs from older donors can be utilized safely in LT, even for younger recipients. Further research is needed to assess if the higher rate of PGD3 associated with use of older donors has an effect on long-term outcomes.

Determinants of radiological patterns and severity in immunocompromised adults with Metapneumovirus infection.

BACKGROUND: Human Metapneumovirus (HMPV) belongs to the Pneumoviridae family and is responsible for respiratory infections. Mild infections are well-recognized in children, while its precise impact in various categories of immunocompromised adults has not been well addressed. RESEARCH QUESTION: We retrospectively studied HMPV infections in immunocompromised adults followed in two large French university medical centers. STUDY DESIGN AND METHODS: We identified immunocompromised adults with positive HMPV Polymerase Chain Reaction (PCR) for 36 months and reviewed their medical charts. For lung transplant recipients (LTR), FEV1 was collected at baseline, during and after infection. Imaging was centralized and chest involvement was categorized by dominant CT patterns. We compared severe patients (requiring oxygen or ventilation) and non hypoxemic patients. RESULTS: Seventy-two patients were included, 27 were LTR, 25 had a hematological malignancy or were hematopoietic stem cell recipients, 20 had another immunocompromised status. Twenty patients (28%) presented a hypoxemic infection, requiring hospitalization and intensive care units transfers in 50/72 (69.4%) and 9/72 (12.5%) respectively, with only one death. Hypoxemia was less pronounced in LTRs (p = 0.014). Finally, age and dyspnea remained independent factors associated with hypoxemia (p < 0.005). The most frequent radiological patterns were bronchopneumonia (34.2%) and bronchiolitis (39.5% and 64.3% in the overall population and in LTRs respectively, p = 0.045). FEV1 improved in LTRs at one month and 85% had recovered their baseline FEV1 within 6 months. INTERPRETATIONS: In immunocompromised adults, HMPV infections required frequent hospitalizations and ICU transfers, while mortality is low. In LTRs, bronchiolitis pattern was predominant with short and long-term favorable outcome.

A randomized double-blind placebo-controlled trial of low-dose interleukin-2 in relapsing-remitting multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) is associated with regulatory T cells (Tregs) insufficiency while low-dose interleukin-2 (IL2LD) activates Tregs and reduces disease activity in autoimmune diseases. METHODS: We aimed at addressing whether IL2LD improved Tregs from MS patients. MS-IL2 was a single-center double-blind phase-2 study. Thirty patients (mean [SD] age 36.8 years [8.3], 16 female) with relapsing-remitting MS with new MRI lesions within 6 months before inclusion were randomly assigned in a 1:1 ratio to placebo or IL-2 at 1 million IU, daily for 5 days and then fortnightly for 6 months. The primary endpoint was change in Tregs at day-5. RESULTS: Unlike previous trials of IL2LD in more than 20 different autoimmune diseases, Tregs were not expanded at day-5 in IL2LD group, but only at day-15 (median [IQR] fold change from baseline: 1.26 [1.21-1.33] in IL2LD group; 1.01 [0.95-1.05] in placebo group, p < 0.001). At day-5, however, Tregs had acquired an activated phenotype (fold change of CD25 expression in Tregs: 2.17 [1.70-3.55] in IL2LD versus 0.97 [0.86-1.28] in placebo group, p < 0.0001). Regulator/effector T cells ratio remained elevated throughout treatment period in the IL2LD group (p < 0.001). Number of new active brain lesions and of relapses tended to be reduced in IL2LD treated patients, but the difference did not reach significance in this trial not powered to detect clinical efficacy. CONCLUSION: The effect of IL2LD on Tregs in MS patients was modest and delayed, compared to other auto-immune diseases. This, together with findings that Tregs improve remyelination in MS models and recent reports of IL2LD efficacy in amyotrophic lateral sclerosis, warrants larger studies of IL2LD in MS, notably with increased dosages and/or modified modalities of administration. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov: NCT02424396; EU Clinical trials Register: 2014-000088-42.

Model of calf muscle tear during a simulated eccentric contraction, comparison between ex-vivo experiments and discrete element model.

The tearing of the muscle-tendon complex (MTC) is one of the common sports-related injuries. A better understanding of the mechanisms of rupture and its location could help clinicians improve the way they manage the rehabilitation period of patients. A new numerical approach using the discrete element method (DEM) may be an appropriate approach, as it considers the architecture and the complex behavior of the MTC. The aims of this study were therefore: first, to model and investigate the mechanical elongation response of the MTC until rupture with muscular activation. Secondly, to compare results with experimental data, ex vivo tensile tests until rupture were done on human cadavers {triceps surae muscle + Achilles tendon}. Force/displacement curves and patterns of rupture were analyzed. A numerical model of the MTC was completed in DEM. In both numerical and experimental data, rupture appeared at the myotendinous junction (MTJ). Moreover, force/displacement curves and global rupture strain were in agreement between both studies. The order of magnitude of rupture force was close between numerical (858 N for passive rupture and 996 N-1032 N for rupture with muscular activation) and experimental tests (622 N ± 273 N) as for the displacement of the beginning of rupture (numerical: 28-29 mm, experimental: 31.9 mm ± 3.6 mm). These differences could be explained by choices of DEM model and mechanical properties of MTC's components or their rupture strain values. Here we show that he MTC was broken by fibers' delamination at the distal MTJ and by tendon disinsertion at the proximal MTJ in agreement with experimental data and literature.

Training and teaching of vagus nerve stimulation surgery: Worldwide survey and future perspectives.

OBJECTIVE: Vagus nerve stimulation (VNS) therapy has been used for more than two decades to treat drug resistant epilepsy and depression and most recently received FDA approval for stroke rehabilitation. Expanding indications will renew the interest in the technique and increase the number of surgeons to be trained. The aim of this study was to survey surgeons with substantial expertise on optimal teaching and training approaches. METHODS: Anonymous forms comprising 16 questions were sent by e-mail to surgeons with substantial expertise. Statistical analyses were used to compare the answers of the most experienced surgeons (>5 years) with the less experienced ones (<5 years). RESULTS: Fully-completed forms were collected from 57 experts from 20 countries. The placement of the helical coils was deemed to be the most difficult step by 36 (63.2%) experts, and the use of optical magnification during this step was deemed necessary by 39 (68.4%) experts. Vocal cord palsy should be largely avoidable with proper surgical technique according to 44 (77.2%) experts. The teaching tool considered the most useful was mentoring (38, 66.7%). The future of VNS surgery teaching was deemed to be in anatomical workshops (29, 50.9%) and surgical simulation (26, 45.6%). Overall, answers did not vary significantly according to experience. CONCLUSIONS: VNS surgery should be mastered by actively participating in dedicated practical training courses and by individual mentoring during actual surgery, which is still the best way to learn. This study highlights the need for a formal training course and possible specific accreditation.

Noninvasive prenatal diagnosis of genetic diseases induced by triplet repeat expansion by linked read haplotyping and Bayesian approach.

The field of noninvasive prenatal diagnosis (NIPD) has undergone significant progress over the last decade. Direct haplotyping has been successfully applied for NIPD of few single-gene disorders. However, technical issues remain for triplet-repeat expansions. The objective of this study was to develop an NIPD approach for couples at risk of transmitting dynamic mutations. This method includes targeted enrichment for linked-read libraries and targeted maternal plasma DNA sequencing. We also developed an innovative Bayesian procedure to integrate the Hoobari fetal genotyping model for inferring the fetal haplotype and the targeted gene variant status. Our method of directly resolving parental haplotypes through targeted linked-read sequencing was smoothly performed using blood samples from families with Huntington's disease or myotonic dystrophy type 1. The Bayesian analysis of transmission of parental haplotypes allowed defining the genotype of five fetuses. The predicted variant status of four of these fetuses was in agreement with the invasive prenatal diagnosis findings. Conversely, no conclusive result was obtained for the NIPD of fragile X syndrome. Although improvements should be made to achieve clinically acceptable accuracy, our study shows that linked-read sequencing and parental haplotype phasing can be successfully used for NIPD of triplet-repeat expansion diseases.Trial registration: NCT04698551_date of first registration: 07/01/2021.

Does increased patient comprehension decrease preoperative anxiety before digestive surgery?

BACKGROUND: There exists a misalignment between the information given by a surgeon and the information retained by the patient. Inability to assimilate relevant information can be a factor of preoperative anxiety. The aim of this study was to assess patients' information retention according to a Fédération de Chirurgie Viscérale et Digestive (FCVD) questionnaire. MATERIALS: From 29 June 2020 to 2 August 2020, a prospective, comparative multicenter study was conducted among 89 patients who were about to undergo digestive surgery. They were included either in a standard group (management in accordance with the usual French guidelines) or experimental group, which received a second consultation, one week before surgery. The day before being operated, all the patients filled out 3 questionnaires analyzing their percentage of retention according to two scales: the Amsterdam Preoperative Anxiety and information Scale (APAIS) and the visual analogue scale for anxiety (VAS-A). RESULTS: Patient comprehension of the FCVD information was 94% and 63% in the experimental and the control groups, respectively (P<0.001). The standard group was significantly more anxious than the experimental group, with VAS-A rates of 6.2 and 4.6 (P=0.014), respectively. On the other hand, according to the APAIS scale, they were similarly anxious, with scores of 11.3 versus 11.9, respectively (P=0.200). CONCLUSION: A second transmission of exhaustive information shortly before digestive surgery was conducive to improved retention. Enhanced comprehension and memorization reduced preoperative anxiety.

PAI-1 protein is a key molecular effector in the transition from normal to PTSD-like fear memory.

Moderate stress increases memory and facilitates adaptation. In contrast, intense stress can induce pathological memories as observed in post-traumatic stress disorders (PTSD). A shift in the balance between the expression of tPA and PAI-1 proteins is responsible for this transition. In conditions of moderate stress, glucocorticoid hormones increase the expression of the tPA protein in the hippocampal brain region which by triggering the Erk1/2MAPK signaling cascade strengthens memory. When stress is particularly intense, very high levels of glucocorticoid hormones then increase the production of PAI-1 protein, which by blocking the activity of tPA induces PTSD-like memories. PAI-1 levels after trauma could be a predictive biomarker of the subsequent appearance of PTSD and pharmacological inhibition of PAI-1 activity a new therapeutic approach to this debilitating condition.

Neurodevelopmental outcome at 2 years of corrected age in fetuses with increased nuchal translucency thickness and normal karyotype compared with matched controls.

OBJECTIVES: Increased nuchal translucency (NT) thickness is an antenatal marker of aneuploidy or malformation that can lead to termination of pregnancy. This study assessed the long-term neurodevelopmental prognosis of infants who had isolated increased NT in utero. METHODS: This was a prospective cohort study of infants with a NT thickness > 95th percentile in the first trimester, but with a normal karyotype and no major anomalies, and controls with normal NT matched for birth weight, Apgar score, place of birth, parity and gestational age at birth. At 2 years of corrected age, all infants underwent the psychometric Brunet-Lézine test to evaluate their developmental quotient (DQ), overall (global) and specifically for the areas of posture, language, coordination and sociability. RESULTS: A total of 203 chromosomally normal infants were included in the increased-NT group and 208 in the control group. The mean global DQ was significantly lower in the increased-NT group than in the control group (108.6 ± 9.7 vs 112.8 ± 8.3; P < 0.0001), but it was within the normal range expected for that age in both groups. Similarly, the mean DQs for coordination, sociability and language, but not for posture, were significantly lower in infants with increased NT than in controls. Only one case with increased NT had a DQ < 70 (defined as severe neurodevelopmental impairment), compared with none in the control group. The difference between the two groups remained significant for a NT threshold ≥ 99th percentile and when the data were adjusted for NT thickness, the infant's sex and the mother's educational level. In the increased-NT group, NT thickness was < 3.5 mm in over half (56%) of the infants, between 3.5 mm and 5 mm in 33% and > 5 mm in 11%, with a mean global DQ of 108.4, 110.1 and 109.7, respectively. CONCLUSIONS: Infants who had isolated increased fetal NT in the first trimester had a significantly lower, but normal, DQ at a corrected age of 2 years, when compared with controls. The findings were independent of the infant's sex, fetal NT thickness and the mother's educational level. © 2020 Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Heavy precipitation and asthma exacerbation risk among children: A case-crossover study using electronic health records linked with geospatial data.

Extreme precipitation events may be an important environmental trigger for asthma exacerbations in children. We used a time stratified case-crossover design and data from a large electronic health record database at the Children's Hospital of Philadelphia (CHOP) to estimate associations of daily heavy precipitation (defined as > 95th percentile of the summertime distribution) with asthma exacerbation among children. We defined control days as those falling on the same day of the week within the same month and year as the case. We restricted our primary analyses to the summer months in years 2011-2016 and used conditional logistic regression models to estimate associations between heavy precipitation and acute asthma exacerbations in both outpatient (primary care, specialty care, and emergency department) and inpatient settings. We investigated numerous individual-level (e.g., age, sex, eczema diagnosis) and environmental measures (e.g., greenspace, particulate matter) as potential effect modifiers. The analysis include 13,483 asthma exacerbations in 10,434 children. Odds of asthma exacerbation were 11% higher on heavy precipitation vs. no precipitation days (95% CI: 1.02-1.21). There was little evidence of effect modification by most measures. These results suggest that heavy summertime precipitation events may contribute to asthma exacerbations. Further research using larger datasets from other health systems is needed to confirm these results, and to explore underlying mechanisms.

[Optimization of the "pharmaceutical consultation" practiced by pharmacists - Review, feedback and future proposals for development since the introduction of the initiative in 2013 focusing on the Calvados area]. / Optimisation des entretiens pharmaceutiques à l'officine ­ Bilan et retour de cette mission mise en place en 2013 et perspectives de développement dans le département du Calvados.

In 2012, a National Agreement of Pharmacists was initiated in France and then amended in 2013 to introduce the "Pharmaceutical consultation". These consultations must be conducted by the pharmacist with the patient in a confidential area in pharmacy or patient residence. The objective is to decrease the frequency of negative side effects of the medical treatments (anti-vitamins k, direct oral anticoagulants and inhaled corticoid) and to improve the correct use of medication therefore assure the safety of the patient. This initiative also recognizes the expertise of the pharmacists who are remunerated with 50 euros per year and per patient from Social Security. This publication is based on a survey conducted in the whole Calvados area and it is based on several individual interviews. It gives a clear picture about how effective the practice has been so far. It shows that the "Pharmaceutical consultation" is currently only proposed to patients by 40% of pharmacists in this area, additionally the practice decreased by 85% in the pharmacies since 2013. However, 8 on 10 pharmacists recognized a real benefit for patients who subscribed for consultation. Independently, the number of non-subsidized conversation initiatives carried out by pharmacists (anti-tobacco, pregnancy, diabetes) are increasing. This finding leads to the investigation of the causes for not practicing the "Pharmaceutical consultation". The causes for not carrying out the consultations were identified, quantified, analysed and classified with a view to proposing short, medium and long time actions to optimize the "Pharmaceutical consultation" in a financially feasible manner. Nine practical proposals were identified and groups in three areas of improvement: communication, remuneration and organization.

Symptomatic progestin-associated atypical grade II meningioma. A first case report.

BACKGROUND: Long-term use of high-dose progestin is known to promote the development of meningioma. Atypical meningioma in a patient under progestin has not previously been reported. CASE REPORT: A 53-year-old right-handed woman presented with focal onset seizures, without impaired consciousness. Medical history featured endometriosis, treated successively by cyproterone acetate 25mg/day for 2 months then 50mg/day for 101 months, and chlormadinone acetate 5mg/day for 68 months then 10mg/day for 83 months. Brain MRI revealed multiple extra-axial lesions suggestive of left central meningioma associated with anterior skull base meningiomatosis. Surgical resection of the left central meningioma was achieved and progestin was withdrawn. Neuropathology diagnosed grade II atypical meningioma. Close clinical and imaging monitoring was implemented without adjuvant oncological treatment. At 25 months, imaging follow-up showed no recurrence of the left central meningioma and a significant regression of all other lesions, except for the right frontal lesion. CONCLUSIONS: Neurosurgeons should be aware of the possible aggressiveness of meningioma in patients under progestin, and particularly those treated by different types of progestin over a long period of time without interruption. This may require systematic close monitoring, to adapt neurosurgical management.

Can Local Enhancement in Earthworms Affect the Outcome of the Standard Earthworm Avoidance Test?

Earthworms exhibit clumping behaviour in and out of the soil. However, it remains unknown if such social behaviour ultimately influences the outcome of ecotoxicological experiments in the laboratory. We performed several overnight avoidance tests to determine whether social behaviour (i.e., local enhancement) is a factor in pollution avoidance behaviour in the earthworm Eisenia fetida. The results showed that there was no clear influence of social behaviour on the choice or avoidance of Cd contaminated soils, although we suspect that 50 mg Cd/kg might not have been high enough to elicit a significant avoidance response. Nevertheless, when offered a choice between clean undisturbed soil and previously inhabited soil, the worms preferred the previously inhabited soil (p < 0.01). While the level of metal pollution investigated in this study did not disrupt or help predict social dynamics, local enhancement, perhaps driven by some sort of habitat imprinting, was successfully documented in Eisenia fetida.